Bonelab, Dental Research Institute, Faculty of Dentistry, University of Toronto, Toronto, ON M5G 1G6, Canada.
Curr Protein Pept Sci. 2012 Mar;13(2):164-79. doi: 10.2174/138920312800493179.
Over the last three decades, V-ATPases have emerged from the obscurity of poorly understood membrane proton transport phenomena to being recognized as ubiquitous proton pumps that underlie vital cellular processes in all eukaryotic and many prokaryotic cells. These exquisitely complex molecular motors also engage in diverse specialized roles contributing to development, tissue function and pH homeostasis within complex organisms. Increasingly, mutations and misappropriation of V-ATPase function have been linked to diseases, ranging from sclerosing bone pathologies and renal tubular acidosis to bone-loss disorders and cancer metastasis. Much remains to be learned about the details of V-ATPase cell and molecular biology; nevertheless, interest in V-ATPases as potential therapeutic targets has burgeoned in recent years. In this review, we present a history of our involvement and contributions to the understanding of V-ATPase structure and function and our nascent and ongoing contributions to translating the knowledge gained from basic research on the nature of V-ATPases into tools for drug discovery. We focus here primarily on the treatment of bone-loss pathologies, like osteoporosis, and present proof-of-concept for a drug screening strategy based on targeting a3-B2 subunit interactions within the V-ATPase complex.
在过去的三十年中，V-ATPases 已经从人们对膜质子转运现象认识不足的模糊状态中脱颖而出，成为普遍存在的质子泵，为所有真核生物和许多原核生物细胞的重要细胞过程提供基础。这些极其复杂的分子马达还参与了多种特殊作用，有助于复杂生物体内的发育、组织功能和 pH 平衡。越来越多的证据表明，V-ATPase 功能的突变和不当利用与疾病有关，从硬化性骨病变和肾小管酸中毒到骨丢失疾病和癌症转移。关于 V-ATPase 的细胞和分子生物学的细节还有很多需要了解；然而，近年来，人们对 V-ATPase 作为潜在治疗靶点的兴趣日益浓厚。在这篇综述中，我们介绍了我们参与和贡献理解 V-ATPase 结构和功能的历史，以及我们在将从 V-ATPase 本质的基础研究中获得的知识转化为药物发现工具方面的初步和正在进行的贡献。我们主要关注骨丢失病变（如骨质疏松症）的治疗，并提出了一种基于靶向 V-ATPase 复合物中 a3-B2 亚基相互作用的药物筛选策略的概念验证。
